A subgroup of microsatellite stable colorectal cancers has elevated mutation rates and different responses to alkylating and oxidising agents.
A subgroup of microsatellite stable colorectal cancers has elevated mutation rates and different responses to alkylating and oxidising agents.
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DOI：
10.1038/sj.bjc.6601740
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发表时间：
2004-04-19
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
遗传性非息肉病性结直肠癌（HNPCC）和一些散发性结直肠癌（CRC）的癌变的早期步骤是获得由DNA错配修复（MMR）基因缺陷引起的“突变体表型”，所述DNA错配修复基因通常维持基因组稳定性。这种突变表型导致碱基置换和小插入/缺失突变增加约100-1000倍，从而驱动致癌作用。它还导致全基因组微卫星不稳定性（MSI），因为无法修复这些小的，难以复制的重复DNA元件内的突变。相比之下，对微卫星稳定（MSS）CRC中增变基因表型的作用知之甚少。在这份报告中，我们已经测量了突变率在11个MSS CRC细胞系，以获得一个估计的突变表型在MSS癌变的患病率。在11个细胞系中，其中3个（27%）具有自发性次黄嘌呤磷酸核糖基转移酶突变率约为背景的10-100倍。当用烷化剂和氧化剂攻击时，存活和凋亡反应的程度是不同的，表明这些细胞系可能代表一种以上的突变体表型。这些数据表明，MSS CRC细胞系的显著部分具有增加的突变率，并且这可能在MSS CRC致癌作用中起作用。
An early step in the carcinogenesis of hereditary non-polyposis colorectal cancer (HNPCC) and some sporadic colorectal cancers (CRCs) is the acquisition of a ‘mutator phenotype’ resulting from defects in DNA mismatch repair (MMR) genes, which normally maintain genomic stability. This mutator phenotype causes an approximately 100–1000-fold increase in base substitutions and small insertion/deletion mutations thereby driving carcinogenesis. It also causes genome-wide microsatellite instability (MSI) due to the inability to repair mutations within these small, hard to replicate, repetitive DNA elements. In contrast, less is known about the role of mutator phenotypes in microsatellite stable (MSS) CRC. In this report, we have measured the mutation rates in 11 MSS CRC cell lines to obtain an estimate of the prevalence of mutator phenotypes in MSS carcinogenesis. Of the 11 cell lines, three of them (27%) possess spontaneous hypoxanthine phosphoribosyltransferase mutation rates approximately 10–100-fold above background. When challenged with alkylating and oxidising agents, the degree of survival and apoptotic responses are different, indicating that these cell lines may represent more than one mutator phenotype. These data demonstrate that a significant portion of MSS CRC cell lines has increased mutation rates and that this may play a role in MSS CRC carcinogenesis.
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